Method of producing n-(4,5-bis-methanesulfonyl-2-methyl-benzoyl)-guanidine, the hydrochloride thereof

ABSTRACT

The present invention relates to an NHE-1 selective Na+/H+ antiporter inhibitor N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloride, to its hydrochloride hydrate, and to a process for the preparation.

The present invention relates toN-(4,5-bismethanesulfonyl-2-methyl-benzoyl)guanidine, hydrochloridehydrate, and to a process for the preparation ofN-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloride andthe hydrochloride hydrate.N-(4,5-Bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloridehydrate is an NHE-1 selective Na⁺/H⁺ antiporter inhibitor.

Sulfonylbenzoylguanidines are known and are described, for example, inEP 0 758 644 A1. These substances are inhibitors of the cellular Na⁺/H⁺antiporter, i.e. they are active ingredients which inhibit the Na⁺/H⁺exchange mechanism of the cells (Düsing et al., Med. Klin. 1992, 87,367-384,) and are consequently good antiarrhythmic agents which aresuitable, in particular, for the treatment of arrhythmia occurring as aconsequence of oxygen deficiency.

The substances exhibit a good cardioprotective action and are thereforeparticularly suitable for the treatment of acute myocardial infarction,infarction prophylaxis, post-infarction treatment, chronic cardiacinsufficiency and for the treatment of angina pectoris. They furthermorecounter all pathological hypoxic and ischaemic damage, enabling theillnesses caused primarily or secondarily thereby to be treated. Theseactive ingredients are likewise highly suitable for preventiveapplications.

Owing to the protective action of these substances in pathologicalhypoxic or ischaemic situations, further possible applications arisetherefrom in surgical interventions for protection of organs withtemporarily reduced supply, in organ transplants for protection of theremoved organs, in angioplastic vascular or cardiac interventions, inischemia of the nervous system, in the therapy of shock states and forthe prevention of essential hypertonia.

These compounds can furthermore also be employed as therapeutic agentsin illnesses caused by cell proliferation, such as arteriosclerosis,diabetes and late complications of diabetes, tumour illnesses, fibroticillnesses, in particular of the lungs, liver and kidneys, and organhypertrophia and hyperplasia. In addition, the compounds are suitablefor diagnostic use for the recognition of illnesses accompanied byincreased activity of the NA⁺/H⁺ antiporter, for example inerythrocytes, thrombocytes or leukocytes.

The compounds can therefore be used as medicament active ingredients inhuman and veterinary medicine. They can furthermore be used asintermediates for the preparation of further medicament activeingredients.

The invention had the object of finding a highly active compound havinga very good oral absorption property.

N-(4,5-Bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloridehydrate has proven to be a highly suitable and highly active substanceand is distinguished by a particularly good oral absorption property.N-(4, 5-Bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloridehydrate is therefore preferably administered in oral form.

The absorption from the digestive tract after oral administration can becalculated by comparison of the concentrations of the administeredactive ingredient determined in the blood plasma after oral andintravenous administration (dose-standardised AUC_(po)/AUC_(iv))[AUC=area under the curve]. The rat exhibited an absorption rate of 98%(of the orally administered radioactively labelled substance).Bioavailabilities of the hydrochloride hydrate of from 88% to 99% werefound in dogs, and 75% and 96% in 2 monkeys. Since the absorption rateis at least equal to or greater than the bioavailability determined,very good absorption has thus also been found in these animal species.

The invention therefore relates toN-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloridehydrate. This invention is to be regarded as a selection invention to EP0 758 644.

Since this substance is very promising, its preparation is of veryconsiderable interest. The preparation of the freeN-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine base and itsanalogues has been described in EP 0 758 644 A1 cited above.

However, the known syntheses comprise a large number of individualsteps, some of which have unsatisfactory yields and which also haveenvironmentally polluting and hazardous reaction conditions, such as,for example, the reaction with methyl mercaptam or the oxidation of thethioether to give the sulfone.

There is therefore great interest in finding an improved process for thepreparation of N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, itshydrochloride and hydrochloride hydrate.

It was therefore likewise an object of the present invention to find anovel synthesis variant for the Na⁺/H⁺ antiporter which is shorter andalso more effective compared with conventional methods.

The invention relates to a process for the preparation of thebenzoylguanidine derivativeN-(4,5-bismethanesulfonyl-2-methylbenzoyl)-guanidine, hydrochloride ofthe formula I

in which Me is methyl, and of the hydrochloride hydrate, which ischaracterised in that firstly, by reaction of the starting compound ofthe formula II

in which

Me is a methyl group, and Q is fluorine or chlorine,

with a methanesulfinate in a nucleophilic substitution on the activatedaromatic ring, the 4-methanesulfonyl group is introduced in a one-stepreaction,

then, in the second step, the compound of the formula III

is converted into an acid chloride and reacted with guanidine to giveN-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine,

and, in the third step, converted into the hydrochloride of the formulaI and/or its hydrochloride hydrate by reaction in aqueous HCl.

The starting compound of the formula II is prepared, for example,starting from 2-bromo-5chlorotoluene by halogen-metal exchange and CO₂treatment to give 4-chloro-2-methylbenzoic acid followed by reaction of4-chloro-2-methylbenzoic acid with chlorosulfonic acid, sodium sulfiteand methyl iodide to give 4-chloro-2-methyl-5-methylsulfonylbenzoic acidor by reaction of 2-bromo-5-chlorotoluene with methanesulfonic acid andthionyl chloride in a Friedel-Crafts-like reaction in the presence of aFriedel-Crafts catalyst to give 4-chloro-2-methyl-4-methylsulfonylphenylbromide followed by exchange of the bromine by a carboxyl group througha palladium-catalysed carbonylation reaction in an autoclave undersuperatmospheric pressure and at elevated temperature to give4-chloro-2-methyl-5-methyl-sulfonylbenzoic acid. The reaction conditionsselected are known from the literature (lit.: Houben-Weyl, Methoden derOrgan. Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag,Stuttgart). However, it is also possible to use other processes whichare known from the literature, but are not explained in greater detailhere, for the preparation of compounds of the formula II.

The term methanesulfinate denotes an alkali metal salt ofmethanesulfinic acid, in particular sodium methanesulfinate or potassiummethanesulfinate, or an alkaline earth metal salt of methanesulfinicacid, in particular calcium methanesulfinate or magnesiummethanesulfinate. Particular preference is given to the use of sodiummethanesulfinate.

The reaction of the compound of the formula II with a methanesulfinate,preferably sodium methanesulfinate, is carried out analogously to themethod of A. Ulman et al., J. Org. Chem. 1989, 54, 4691-4692. Thereaction is preferably carried out in a polar solvent and at reactiontemperatures between 10 and 200°, preferably between 50 and 180°,particularly preferably between 80 and 140°. Particularly preferredsolvents are dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF) or1-methyl-2-pyrrolidone (NMP), very particularly preferably DMF or NMP.The methanesulfinate is generally employed in excess. Under the saidreaction conditions, exclusively the4,5-bismethanesulfonyl-2-methylbenzoic acid of the formula III isformed.

The guanidination of the compound of the formula III in step 2 is notrestricted to the acid chloride method, in which, for example, thecompound of the formula III is reacted with thionyl chloride to give theacid chloride and further with guanidine. There is a large number ofmethods known from the literature which enable the introduction of aguanidino group (for example in the standard works, such as Houben-Weyl,Methoden der organischen Chemie [Methods of Organic Chemistry],Georg-Thieme-Verlag, Stuttgart).

For a guanidination in step 2, it is possible, inter alia, to react thefree acid of the formula III with N-(benzyloxycarbonyl)guanidine, withthe subsequent removal of the benzyloxycarbonyl protecting group(abbreviation=Z) liberating the guanidino group, as described in DE 19919 349. For the preparation of benzyloxycarbonylguanidine, see M.Goodman et al., PCT Int. Appl. WO 9852917, 1998, K. Nowak, Rocz. Chem.1969, 43, 231-232 or R. Krug and K. Nowak, Rocz. Chem. 1967, 41,1087-1091). The coupling is carried out with the aid of the knownMukaiyama method, cf. T. Mukaiyama, Angew. Chem., Int. Ed. Engl. 1979,18, 707-721. The removal of the Z protecting group by catalytichydrogenation can be carried out under the general conditions for thispurpose (lit.: T. W. Greene, P. G. M. Wuts, Protective Groups in OrganicChemistry, 2nd Edn., Wiley, New York 1991 or P. J. Kocienski, ProtectingGroups, 1st Edn., Georg Thieme Verlag, Stuttgart—New York, 1994)

The base N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine prepared inaccordance with the invention in steps 1 and 2 can also be convertedinto a salt by methods known from the literature by means of acids otherthan HCl. The acids which are suitable for this purpose are disclosed inEP 0 785 644.

In the method described in EP 0 758 644 for the preparation ofsulfonylbenzoylguanidines, the sulfonyl group in the para-position tothe carboxyl group is introduced via a nucleophilic halogen-sulfur alkylexchange in addition to subsequent oxidation of the resultant thiophenolether.

The process now present in this invention introduces the sulfonyl groupin he para-position in a single-stage reaction step. The number ofsynthesis steps and the preparation costs associated therewith arereduced. Furthermore, the reaction with methyl mercaptam and theoxidation, which make particular technical safety measures necessary ona large industrial scale due to the possibility of peracid formation,are absent.

An effective process is thus available for the preparation of N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloride and itshydrochloride hydrate which is significantly improved compared with theprocess known hitherto, both with respect to the number of synthesissteps and also with respect to the overall yield.

Even without further comments, it is assumed that a person skilled inthe art will be able to utilise the above description in the broadestscope. The preferred embodiments should therefore merely be regarded asdescriptive disclosure which is absolutely not limiting in any way.

The complete disclosure content of all applications and publicationsmentioned above and below are incorporated into this application by wayof reference.

All temperature data above and below are given in ° C.

EXAMPLE 1. Synthesis of 4,5-Bismethanesulfonyl-2-methylbenzoic Acid

6 kg of 4-chloro-2-methyl-5-(methylsulfonyl)benzoic acid are dissolvedin 15 l of N,N-dimethylformamide (DMF) at room temperature (25°) andsubsequently warmed to 50°. 3.6 kg of sodium methanesulfinate are addedto this solution. The internal temperature is then raised to 120° andstirred at this temperature for 2 days, with a further 3 kg of sodiummethanesulfinate being added after 24 hours. After cooling to 25°, thereaction mixture is introduced into 40 l of water, and 300 g ofactivated carbon and 1 kg of kieselguhr are added. 5 l of ice are addedto the filtrate, and 3.5 l of concentrated hydrochloric acid are addeddropwise (pH=1). Recrystallisation from 2-propanol gives 3.8 kg of4,5-bismethanesulfonyl-2-methylbenzoic acid; m.p. 234-235°.

2. Synthesis of N-(4,-Bismethanesulfonyl-2-methylbenzoyl)guanidine

2.1 Synthesis of the Acid Chloride

15 l of thionyl chloride are initially introduced at 40°, and 50 ml ofDMF are added. 3.8 kg of 4,5-bismethanesulfonyl-2-methylbenzoic acid areslowly introduced with stirring, and the mixture is then stirred at theboiling point for 1 hour. After cooling, the excess SOCl₂ is removed,and the residue is codistilled a number of times with 5 l of toluene,giving 4, 5-bismethanesulfonyl-2-methylbenzoyl chloride, which isreacted further as the crude product.

2.2. Synthesis of the Guanidine

1.4 kg of sodium are dissolved in 15 l of boiling methanol under aprotective gas and diluted with a further 10 l of methanol. 5.9 kg ofguanidinium hydrochloride are added to the solution, cooled to 20-22°,and the mixture is stirred for 1 hour. The resultant sodium chloride isthen filtered off, and the solution is evaporated. The residue iscodistilled with toluene and then taken up in 10 l of DMF.

2.3 Synthesis of N-(4,5-Bismethanesulfonyl-2-methylbenzoyl)guanidine

A solution of 4,5-bismethanesulfonyl-2-methylbenzoyl chloride, preparedas described in 2.1., in 5 l of DMF is added dropwise at 12° to theguanidine solution prepared as described in 2.2. The reaction mixture isstirred at 20° for 5 hours, and 45 l of cold water (0-50) are addedslowly. The deposited crystals are filtered off and rinsed withice-water, acetonitrile and diethyl ether. The crude crystals aredissolved in 315 l of hot acetonitrile/water (20:1). The solution istreated with 200 g of activated carbon, filtered and cooled to 0°,giving N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine as theacetonitrile adduct in a yield of 64.8%; m.p. 233-2340 °.

3.1. Synthesis of N-(4,5-Bismethanesulfonyl-2-methylbenzoyl)guanidine,Hydrochloride Hydrate

2.7 kg of N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine aresuspended in 25 l of water at 60°, and 10.6 l of 1N HCl solution areadded. On warming to 80°, a clear solution is obtained. The solution isallowed to cool slowly, with crystallisation beginning at 50°, givingN-(4, 5-bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloridehydrate in a yield of 97%, m.p. 181-188 °.

3.2. Synthesis of N-(4,-Bismethanesulfonyl-2-methylbenzoyl)guanidine,Hydrochloride

The N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloridehydrate obtained from 3.1. is dried to constant weight at 120° underreduced pressure, givingN-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloride.

3.3. Synthesis of N-(4,5-Bismethanesulfonyl-2-methylbenzoyl)guanidine,Hydrochloride

2.7 kg of N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine aresuspended in 25 l of ethanol at 60°, and 10.6 l of 1N HCl solution areadded. On warming to 80°, a clear solution is obtained. The solution isallowed to cool slowly, with crystallisation beginning at 50°, The N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloride obtainedis subsequently dried to constant weight at 60°, givingN-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloride.

What is claimed is: 1.N-(4,5-Bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloridehydrate.
 2. A process for the preparation ofN-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloride ofthe formula I,

in which Me is methyl, and of the hydrochloride hydrate, which ischaracterised in that firstly, by reaction of the starting compound ofthe formula II

in which Me is a methyl group, and Q is fluorine or chlorine, with amethanesulfinate in a nucleophilic substitution, the 4-methanesulfonylgroup is introduced in a one-step reaction, then, in the second step,the compound of the formula III

is converted into the acid chloride and reacted with guanidine to giveN-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, and, in the thirdstep, converted into the hydrochloride of the formula I and/or thehydrochloride hydrate by reaction in aqueous HCl.
 3. A process accordingto claim 2, characterised in that sodium methanesulfinate is used in thefirst step.
 4. A process according to claim 2, characterized in that apolar solvent is used in the first step.
 5. A process according to claim2, characterized in that a reaction temperature of between 80 and 140°is set in the first step.